Significance: In 2016, 224,390 new cases of LC and 158,080 related deaths are expected in the US. Of new LC cases ~85% are non-small cell lung cancer (NSCLC) and 70% of these are diagnosed with metastatic/ locally advanced/ inoperable LC with a 5-yr survival of less than 17%. A new approach is required to reduce the overall death rates in this devastating disease. Efficacious therapies targeting EGFR, ALK and ROS translocations and vEGF are used in standard of care (SoC). However, they are only effective in <10% of the overall NSCLC population. FDA approved companion diagnostics are used to identify patients that may receive benefit from these drugs. In spite of these advances, no therapy is curative in advanced disease and median life expectancy for metastatic NSCLC remains at ~12 mths. Hypothesis: We have identified GP88, an 88 kDa glycoprotein autocrine intimately involved in cellular deregulated growth leading to tumor formation. The PI, demonstrated GP88?s critical role in the biological process of cancer tumorigenesis and survival, its overexpression in LC tumors while it is not expressed in normal lung tissue, its secretion into biological fluids at increased levels in LC patients compared to healthy individuals. Thus using a tissue test to identify tumors that express GP88 and then treating these patients with an antibody that neutralizes GP88 and therefore blocks its autocrine effect on cancer cells will a) inhibit tumor growth and b) increase the efficacy of current LC drugs. Supporting Evidence: Pathological studies established GP88 tumor expression as a predictive marker for recurrence. Clinical studies showed LC patients with progressive disease have elevated GP88 serum levels compared to healthy individuals. In Vivo studies demonstrated that AG1, a recombinant anti-GP88 can reduce the growth of human LC xenografts in mice and potentiate the effect of SoC drugs. Strategy and Approach: We will carry out a phase I clinical trial using AG1 to determine safety and recommended phase 2 dose. In addition, we will require tissue collection and serial blood sampling on all patients to evaluate for GP88 expression (tissue) and concentration (blood) in enrolled patients and expansion cohorts of NSCLC and mesothelioma, diseases demonstrated to express GP88 correlated with outcome. The IHC test measures GP88 expression in tumor tissue to identify patients with tumors expressing GP88. The serum GP88 EIA test can provide real time monitoring of disease status in the SoC. Specific aim 1: Manufacture 300gms of GMP AG1 for the Phase I clinical studies Specific Aim 2: Perform a Phase I clinical study in (a) patients with solid tumors to determine maximum tolerated dose/ optimum biological dose and (b) expansion cohorts with LC and mesothelioma patients. Overall Impact: Blocking the action of GP88 in aggressive cancer such as LC using a neutralizing antibody will 1) inhibit tumor growth 2) potentiate standard of care drugs. There is compelling biological and clinical evidence to suggest that GP88 is therapeutic target with companion diagnostics for NSCLC that could impact LC treatment and improve survival of patients with NSCLC. Lay outline In 2016, 224,390 new cases of LC and 158,080 related deaths are expected in the US. The majority of these are non-small cell lung cancer (NSCLC) that are diagnosed with metastatic cancer and only 17% of these will be alive at 5yrs post diagnosis. Drugs that are effective in this disease are only useful in less than 10% of the NSCLC population and no curative therapies exist. A new approach that will benefit a larger population and provides increased life expectancy needs to be developed. We have identified GP88, a glycoprotein that is produced by cancer cells and stimulates growth and survival of the same cancer cells leading to tumor formation. GP88 is found in LC but not normal lung tissue. There is compelling biological and clinical evidence to suggest that GP88 is therapeutic target with companion diagnostics for NSCLC that could impact treatment and improve survival of patients with NSCLC. We have developed a tissue test to identify which tumors express GP88 and an anti-GP88 (AG1) to block the action of GP88 on tumor tissues to a) inhibit tumor growth and b) increase the efficacy of current LC drugs. Additionally, a blood test has been developed to monitor patients while on treatment. Using AG1 as the therapy with two companion diagnostic tests we will carry out a phase I clinical trial to determine safety of AG1 in humans and will collect tumor tissue and blood on all patients to evaluate for GP88 expression (tissue) and concentration (blood).